tbuckley/cabot-search huggingface dataset:
Abstract 5580: Incorporation of pro-memory transcription factors in fourth generation CARs enhances CAR T cell immunotherapy against solid tumors in an immunocompetent murine model
Authors: Steven J. Reed, Samantha J. Tower, Ryma Toumi, Vandana Kalia, Surojit Sarkar
Journal: Cancer Research (2022)

Abstract A major obstacle in current T cell-based immunotherapy against solid tumors is the widely observed T cell exhaustion and loss of functionality within the tumor microenvironment (TME). We, and others, have demonstrated that chronic antigenic signaling is the predominant factor that drives TCR tumor-reactive, and CAR T cell exhaustion in the TME. To combat this exhaustion, we have engineered CD19-targeted third generation CAR constructs to express pro-memory transcription factors associated with longevity, polyfunctionality and/or enhanced responsiveness to immune checkpoint blockade in cancer immunotherapy. Using an immunocompetent murine model of syngeneic solid tumors expressing truncated human-CD19 (hCD19t), we demonstrate that ectopic expression of pro-memory transcription factors in the 4th generation transcription factor-CARs (TF-CARs) augments CAR T cell therapeutic efficacy against solid tumors. Amongst CAR T cells recovered from established solid tumors, the 4th generation TF-CAR T cells retained a memory-precursor effector (MPEC) T cell like phenotype, while the 3rd generation CAR T cells largely displayed a terminally exhausted phenotype (TEx). Importantly, the inclusion of select pro-memory transcription factors did not compromise CAR T cell proliferation or expression of the effector cytokines IFN-γ and TNFα following restimulation. In addition to superior control of primary tumors, the TF-CAR T cells instilled greater long-term protection from tumor relapse in mice, which cleared primary tumors (6/7) compared to 3rd generation CAR T cells (3/7). Collectively, these data present incorporation of pro-memory transcription factors as an attractive engineering strategy to intrinsically combat CAR T cell exhaustion in the TME and promote long-term CAR T cell memory and protection from tumor relapse. Citation Format: Steven J. Reed, Samantha J. Tower, Ryma Toumi, Vandana Kalia, Surojit Sarkar. Incorporation of pro-memory transcription factors in fourth generation CARs enhances CAR T cell immunotherapy against solid tumors in an immunocompetent murine model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5580.
Abstract 4027: Dual MEK and AKT inhibition suppresses pancreatic cancer growth and migration
Authors: Jarrid Jack, Alexandra Pierce, Bailey Bye, McKinnon Walsh, Prabhakar Chalise, Michael N. VanSaun
Journal: Cancer Research (2022)

Abstract Pancreatic cancer is one of the deadliest cancers, due to late diagnosis and very few available therapeutic treatments. The Kras gene is frequently mutated in pancreatic cancer, but previous clinical trials using RAS inhibitors have proven ineffective. Additionally, many drug treatments targeting the MAPK pathway have shown little success due to the inherent drug resistance of pancreatic cancer cells and to acquired resistance through activation of alternative proliferative pathways such as JAK-STAT and PI3K-AKT. Our pathway analysis after MEK inhibition in pancreatic cancer cells displayed sustained and/or upregulation of AKT activity in multiple cell lines. Therefore, we hypothesize that a combination treatment of Trametinib and Omipalisib would block two prominent mitogenic pathways (MEK and AKT, respectively) to suppress cancer cell proliferation and migration. Multiple analyses including Western blot, clonogenic, 5-Ethynyl-2’-Deoxyuridine (EDU), and scratch migration assays were employed to determine the augmentation of cellular function in murine and anthropic pancreatic cancer cell lines after single or combination treatment with Trametinib and/or Omipalisib. Results demonstrated that application of Omipalisib alone was successful at blocking pAKT but failed to suppress pERK. Conversely, Trametinib alone selectively inhibited pERK but did not affect pAKT levels. The combination treatment successfully suppressed both pathways in relatively low quantities, indicating their efficacy as a dual therapeutic. Dual therapy was further effective at inhibiting cell growth as evidenced by clonogenic and EdU assays. Recovery and closure from an in vitro scratch wound was also significantly inhibited with combination of Omipalisib and Trametinib. In vivo studies demonstrated that both the pancreatic xenograft mean tumor growth and final tumor size were significantly reduced in response to the combination treatment compared to vehicle. In conclusion, dual therapy with Omipalisib and Trametinib showed a greater anti-tumor efficacy than treatment with either drug alone. Currently, we are determining the prolonged effectiveness of this combination treatment program in genetically-engineered mouse models. If successful, a pharmacological application of Omipalisib and Trametinib has the potential to provide a beneficial therapeutic option to pancreatic cancer patients. Citation Format: Jarrid Jack, Alexandra Pierce, Bailey Bye, McKinnon Walsh, Prabhakar Chalise, Michael N. VanSaun. Dual MEK and AKT inhibition suppresses pancreatic cancer growth and migration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4027.
Abstract 2212: Racially disparate serum levels of inflammatory cytokines, satiety and stress hormones, and exosomal microRNAs in women with or without a breast cancer diagnosis
Authors: Sarabjeet Kour Sudan, Kunwar Somesh Vikramdeo, Amod Sharma, Sachin Kumar Deshmukh, Sanjeev Kumar Srivastava, Teja Poosarla, Nicolette P. Holliday, Donna L. Dyess, Ajay P. Singh, Seema Singh
Journal: Cancer Research (2022)

Abstract Breast cancer (BC) is the most common non-cutaneous malignancy and the second leading cause of cancer-related death in American women. Health disparities in incidence and clinical outcome are also reported among different racial groups, most notably African American (AA) women, who are often diagnosed at a young age with aggressive BC and exhibit greater mortality than Caucasian American (CA) women. Since socioeconomic difficulties can have tremendous impact on psychophysiology besides limiting the access to optimal healthcare, we examined the serum levels of stress (cortisol) and satiety (leptin) hormones as well as inflammatory cytokines (resistin and interleukin-6/IL-6) in AA and CA women. To observe a potential epigenomic connection, we also performed profiling of a targeted set of exosomal microRNAs in serum samples. The study was conducted under an Institutional Review Board (IRB) approved protocol. All subjects participated voluntarily, and their consents were obtained. Serum levels of resistin, IL-6, leptin, and cortisol were quantified by Enzyme linked Immunosorbent Assay (ELISA) using commercial kits. Exosomes were isolated using precipitation method and recovered by standard centrifugation. Total RNA was isolated from exosomal preps and subjected to stem-loop RT-PCR for quantitation of a set of inflammation-associated microRNAs. We found that the levels of resistin, leptin, IL-6 and cortisol were higher in women with a BC diagnosis than non-BC subjects. Moreover, AA women with or without BC showed significantly higher levels of these cytokines and hormones in their serum as compared to the CA women with or without a BC diagnosis, respectively. We also observed differential expression of several microRNAs in serum of BC women as compared to their normal counterparts, of which five (miR511, miR33a, miR27a, miR6794, miR143-3p) exhibited highest presence in serum exosomes of AA women with BC. Together, these findings suggest that relatively greater exposure of minority women to social stressors may have epigenomic consequences and may potentially be linked to the observed BC racial health disparities. Citation Format: Sarabjeet Kour Sudan, Kunwar Somesh Vikramdeo, Amod Sharma, Sachin Kumar Deshmukh, Sanjeev Kumar Srivastava, Teja Poosarla, Nicolette P. Holliday, Donna L. Dyess, Ajay P. Singh, Seema Singh. Racially disparate serum levels of inflammatory cytokines, satiety and stress hormones, and exosomal microRNAs in women with or without a breast cancer diagnosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2212.
Abstract 5675: Pathological crosstalk between osteocytes and breast cancer cells in bone metastasis
Authors: Manish Adhikari, Hayley Sabol, Aric anloague, Sharmin Khan, Jesus Delgado-Calle
Journal: Cancer Research (2022)

Abstract Bone provides an ideal niche for breast cancer cells (BCa) to reside and proliferate and is a frequent site of BCa metastasis. Osteocytes are the most abundant skeletal cells and permanent residents of bone. However, the role of osteocytes in BCa bone metastasis remains understudied. Here, we investigated the crosstalk between metastatic BCa cells and osteocytes. In vitro cultures revealed that conditioned media (CM) derived from metastatic E0771 BCa cells decreased by 50% the number of alive MLO-A5 and MLO-Y4 osteocyte-like cell lines. BCa cells modestly increased osteocyte apoptosis (2% vs. 6%, alone vs. exposed to BCa, respectively). Treatment with DEVD, a caspase 3 inhibitor, blocked osteocyte apoptosis but did not prevent the decrease in osteocytes induced by BCa. Thus, we studied osteocyte senescence, a process that causes irreversible cell cycle arrest and profound changes in gene expression. We found that BCa-CM upregulated the expression of markers of senescence markers (p16, p21) and senescence-associated secretory phenotype (Mmp13, Mmp9, Vcam-1) in osteocyte-like cell lines. Similarly, BCa-CM increased the expression of senescent markers in ex vivo bone organ cultures containing primary osteocytes. Osteocytes increased BCa cell proliferation by increasing cyclin D1 expression Through both cell-to-cell interactions and secretion of soluble factors., osteocytes increased BCa cell proliferation by increasing cyclin D1 expression. Moreover, osteocyte-derived CM stimulated BCa cells migration and invasion capabilities and upregulated the expression of genes involved in migration (Vcam-1 and N-cadherin). Co-culture with stromal cells also stimulated BCa cell proliferation, invasion, and migration. However, the increases induced by stromal cells were four-fold lower than those seen with osteocytes. Overall, our results suggest that BCa cells reprogram osteocytes, which acquire a senescent phenotype, whereas osteocytes produce factors that stimulate tumor growth, migration, and invasion. Together, these findings support the existence of a crosstalk between osteocytes and BCa cells in the metastatic niche that favors the progression of breast cancer in bone. Future studies are warranted to examine the contribution of osteocyte senescence and osteocytes-derived factors in animal models of breast cancer metastasis. Citation Format: Manish Adhikari, Hayley Sabol, Aric anloague, Sharmin Khan, Jesus Delgado-Calle. Pathological crosstalk between osteocytes and breast cancer cells in bone metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5675.
Abstract 3496: Transcriptomic classification of lung adenocarcinoma identifies a novel subgroup with a poor survival prognosis
Authors: Khaled Bin Satter, Paul MH Tran, Lynn KH Tran, John Nechtman, Nikhil Patel, Bruno Santos, Diane Hopkins, Nagla Abdel Karim, Jin-Xiong She, Sharad B. Purohit
Journal: Cancer Research (2022)

Abstract Lung adenocarcinoma is one-half of all lung cancer and the third deadliest cancer in the world. The traditional classification of lung adenocarcinoma involves invasiveness, growth pattern, presence of mucin, and other histological features. However, this classification provides limited prognostic predictability. Molecular profiles based The Cancer genome Atlas lung adenocarcinoma cohort classified the tumors into the terminal respiratory unit (TRU), proximal proliferative (PP), and proximal infiltrative (PI) based on unsupervised classification, which did not address clinical applicability to the classification. Here, we developed an unsupervised classification with Density-based UMAP (DBU), which identified four transcriptomic profiles for lung adenocarcinoma (Transcriptomic profile, TP1-TP4). We identified a gene signature with 299 genes to develop a supervised classifier, called Ensemble Transcriptomic classifier (ETC), to identify these four subgroups within the total cohort. All TP1 is PI. TP2 is 49.0% TFU and 45.0% PP. TP3 is 76.2% PI and 23.8% PP. TP4 is 54.5% TFU and 45.5% PI. TP1 is characterized by neuroendocrine-like features and clusters with large cell neuroendocrine tumors in cluster analysis. TP3 is squamous-like enriched with cell cycle and DNA repair high and worse prognosis and groups with squamous cell carcinoma in cluster analysis. TP2 has high immune cell infiltration, and TP4 showed low mutational burden and low immune cell infiltration. We validated these subgroups identified in the TCGA cohort in a microarray meta-dataset with DBU, ETC. This classification showed four subgroups in lung adenocarcinoma, which shows potential clinical actionable findings. Citation Format: Khaled Bin Satter, Paul MH Tran, Lynn KH Tran, John Nechtman, Nikhil Patel, Bruno Santos, Diane Hopkins, Nagla Abdel Karim, Jin-Xiong She, Sharad B. Purohit. Transcriptomic classification of lung adenocarcinoma identifies a novel subgroup with a poor survival prognosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3496.
Abstract 1842: Drug repurposing screen reveals glioblastoma cell line susceptibility to statins
Authors: Dylan S. Harwood, Signe R. Michaelsen, Bjarne W. Kristensen
Journal: Cancer Research (2022)

Abstract Background: The standard therapy for glioblastoma patients is tumor resection followed by radiotherapy and temozolomide chemotherapy. Although glioblastoma has been extensively molecularly profiled along with other cancers, this knowledge has not yet been translated into improved survival outcomes. We used a bioinformatics approach to identify potential novel therapeutic strategies for glioblastoma. Objectives: Comprehensive online datasets which have assessed up to 1376 cancer cell lines in multiple ways were interrogated to identify potential drug candidates for glioblastoma. Methods: Datasets included were from the cancer cell line encyclopedia (mRNA expression), the Achillies project (cell viability following Crispr-Cas9 knockout) and PRISM (drug treatment). A t-test comparing cell viability of glioblastoma cell lines versus other cancers was used to identify potential drug candidates, followed by the use of multiple statistical tools to investigate potential mechanism of action and status of biomarkers. Results: Fluvastatin and pitavastatin were amongst the drugs with the most significant effects against glioblastoma cell lines while also being FDA approved. These effects were found in both glioblastoma cells and other cancer types with a mesenchymal-like expression phenotype. The anti-cancer properties of statins have previously been attributed to the inhibition of HMG-Coa reductase. Here, we found their effects correlated with the gene knockout of UBIAD1, which participates in non-mitochondrial ubiquinone and menaquinone-4 synthesis. We tested the effects of statins on patient-derived glioblastoma cell lines with a mesenchymal (n = 2) and non-mesenchymal phenotype (n=2). Mesenchymal-like glioblastoma cells lines were found to be particularly susceptible to multiple statins. Conclusion: Statins appeared to be especially effective against glioblastoma lines and the effect could be linked to the direct or indirect inhibition of UBIAD1. In vitro validation of this finding is ongoing. Citation Format: Dylan S. Harwood, Signe R. Michaelsen, Bjarne W. Kristensen. Drug repurposing screen reveals glioblastoma cell line susceptibility to statins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1842.
Abstract 2485: Applications of multimodality ex-vivo tissue imaging to improve breast cancer diagnosis and treatment
Authors: Corazon Avila, Gregory Karczmar, Devkumar Mustafi
Journal: Cancer Research (2022)

Abstract Breast cancer is the most common malignancy affecting women worldwide. Existing models being used to study breast cancer include the Patient-Derived Tumor Organoid (PDTO) Model and the Patient-Derived Tumor Xenograft (PDTX) Model. Both models involve the surgical removal of a tumor from a patient which then undergoes processing to grow an organoid or injected into mice to test different therapies outside the body. However, these models not only take a considerable amount of time to develop properly, but in many cases aren’t representative of the most aggressive tumor cells present within a heterogeneous tissue sample in order to draw the most clinically accurate conclusions of a tumor's response to therapy. In order to advance clinical research, more efficient culture systems that are faster growing and more representative of biological characteristics in-vivo are needed. Previous work from the Karczmar Lab discovered that high-resolution magnetic resonance imaging (MRI) can detect regions of aggressive cancer in biopsy specimens from mouse models, and give additional information on characteristics including cell density, tissue composition, and cancer stage. With this recent discovery, it is hypothesized that ex-vivo imaging could be used to identify aggressive tumor cells in human heterogeneous breast cancer tissue samples to produce higher quality and faster-growing models for testing new therapies and guiding individual patient therapy for breast cancer. The primary aim for this study was to specifically identify image-based markers for regions of aggressive cancer by comparing ex-vivo high-resolution MRI with histology and immunohistochemistry in 3D. Distant normal (DN) and tumor (Tu) tissue samples from breast cancer patients were obtained and imaged using T2-weighted 3D Rapid Imaging with Refocused Echoes (RARE) and stained using hematoxylin and eosin (H&amp;E), commonly used by pathologists to diagnose cancers. Then, the ex-vivo T2-weighted 3D RARE images were correlated to the histopathological H&amp;E staining and confirmed by breast radiologists and pathologists. Preliminary results revealed that high-resolution MR imaging detects mammary glands, ducts, and white adipose tissue in DN tissue samples and regions of invasive cancer, including ductal carcinoma in-situ (DCIS) and necrosis, in Tu tissue. Based on these results, aggressive cancer regions were proven to be identified using image-based guidance and potentially be extracted using core-needle biopsy to improve PDTO and PDTX models for studying breast cancer and advancing individual patient therapy. Citation Format: Corazon Avila, Gregory Karczmar, Devkumar Mustafi. Applications of multimodality ex-vivo tissue imaging to improve breast cancer diagnosis and treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2485.
Abstract 5514: Therapeutic potential of activated natural killer cells in nasopharyngeal carcinoma
Authors: Shinyee Hui, Kwok Wai Lo, Mingjing Xu, Siu Tim Cheung
Journal: Cancer Research (2022)

Abstract One of the key features of nasopharyngeal carcinoma (NPC) is dense lymphocyte infiltration. Despite elevated lymphocyte populations in tumor microenvironment, these lymphocytes have modest killing activity. One of the possible speculations is constitutive STAT3 overexpression within NPC microenvironment which results in immunosuppression of cytolytic immune cells. Natural killer (NK) cells act as first line defense of innate immunity through cytolytic killing of virus-infected cells and/or cancer cells. Unlike T cells, NK killing does not require antigen presentation and therefore would be effective even for MHC defective cancers. This makes NK therapy attractive in form of autologous and allogeneic transfer. Here we hypothesized that activated NK cells would show enhanced anti-NPC activity. We also sought to investigate the potential of combined NK with STAT3 inhibitor in NPC treatment. In this study, NK cells from peripheral blood mononuclear cells (PBMC) of healthy donors (N=3) were isolated and expanded. Three Epstein Barr Virus (EBV) positive NPC cell lines (NPC43, C666-1, C17) were employed in this study. Naïve and activated NK cells were subjected to NPC coculture at various effector: target (E:T) cell ratios. In combination treatment with NK cells, a small molecule inhibitor Napabucasin was employed for STAT3 treatment. NK killing activity was assessed through flow cytometry analysis of NPC cell death. The current study demonstrated significant elevation of NK activation marker expressions after 4 weeks of ex vivo expansion (CD69 34.7±2.3 fold, p=0.002; NKG2D 4.2±0.8 fold, p=0.018). Concomitantly, ex vivo activated NK cells demonstrated augmented killing activity against NPC cells at a dose-dependent manner, compared to their naïve status (p&amp;lt;0.001). In NPC43, net cytotoxicity of expanded NK was 35.5±7.2% compared to naïve NK with only 2.5±4.3% (p=0.003). NPC43 was most sensitive towards NK killing, followed by C666-1, then C17. This corresponds to NPC43’s low PD-L1 protein expression, a known downstream STAT3 target and immune checkpoint molecule. In addition, activated NK could kill chemoresistant NPC cells indiscriminately compared to the paralleled parental cells (18.5±2.3% and 16.1±3.8%, p=0.589). Importantly, augmented NPC43 cell death was observed in combined treatment (47.1±2.1%) compared to single treatment (NK alone: 9.2±6.5%; Napabucasin alone: 25.0±4.5%). In summary, this work demonstrated encouraging therapeutic potential of both NK therapy and in combination with STAT3 inhibitor Napabucasin for NPC treatment. Citation Format: Shinyee Hui, Kwok Wai Lo, Mingjing Xu, Siu Tim Cheung. Therapeutic potential of activated natural killer cells in nasopharyngeal carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5514.